{"gene":"COMMD1","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2003,"finding":"MURR1/COMMD1 inhibits NF-κB activity in resting CD4+ T cells by stabilizing IκB-α and preventing its proteasomal degradation; knockdown of MURR1 increased NF-κB activity and decreased IκB-α by facilitating phospho-IκB-α degradation by the proteasome, resulting in increased HIV-1 replication in primary resting CD4+ lymphocytes.","method":"RNA interference knockdown in primary resting CD4+ T cells, proteasome inhibitor assays, NF-κB reporter assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi knockdown with defined molecular phenotype (IκB-α stabilization, NF-κB activity, HIV replication), replicated across multiple experimental systems in a high-impact journal","pmids":["14685242"],"is_preprint":false},{"year":2003,"finding":"XIAP interacts with MURR1/COMMD1 and acts as its ubiquitin ligase, forming K48-linked polyubiquitin chains on MURR1 that promote its proteasomal degradation; XIAP-deficient mice had reduced copper levels while MURR1 suppression increased intracellular copper, indicating XIAP and MURR1 have opposing effects on copper homeostasis.","method":"Co-immunoprecipitation, ubiquitin chain analysis, Xiap-knockout mouse tissues, copper measurements in cells and tissues","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitin chain typing (K48), genetic knockout model, replicated across cell and animal systems","pmids":["14685266"],"is_preprint":false},{"year":2003,"finding":"MURR1/COMMD1 directly interacts with the Wilson disease protein ATP7B in vitro and in vivo; this interaction is mediated via the copper-binding amino terminus of ATP7B and is specific for this copper transporter, placing MURR1 in the pathway of hepatic biliary copper excretion.","method":"In vitro binding assay, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstitution plus in vivo Co-IP, interaction domain mapped, replicated by multiple subsequent studies","pmids":["12968035"],"is_preprint":false},{"year":2003,"finding":"MURR1/COMMD1 interacts with delta, beta, and gamma subunits of the epithelial sodium channel (ENaC) and inhibits amiloride-sensitive sodium current in a dose-dependent manner when co-expressed in Xenopus oocytes; deletion of the last 59 amino acids of deltaENaC abolished inhibition.","method":"Yeast two-hybrid screen, GST pulldown, co-immunoprecipitation, Xenopus oocyte electrophysiology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — electrophysiology (functional readout), pulldown, Co-IP, domain deletion mapping in single study with multiple orthogonal methods","pmids":["14645214"],"is_preprint":false},{"year":2003,"finding":"MURR1/COMMD1 protein is absent in livers of copper toxicosis-affected Bedlington terriers; in cells the protein localizes to cytosol and membrane fractions and is associated with a vesicular compartment, suggesting a role in vesicular copper sequestration.","method":"Western blot with polyclonal antibodies, indirect immunofluorescence, cell fractionation","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct localization experiment by fractionation and immunofluorescence, single lab, two methods","pmids":["14568250"],"is_preprint":false},{"year":2005,"finding":"COMMD proteins form a novel family defined by the conserved COMM domain, which functions as an interface for protein-protein interactions including homo- and heteromeric complex formation. COMMD1 (MURR1) suppresses NF-κB not by affecting nuclear translocation or DNA binding but by acting in the nucleus to affect NF-κB association with chromatin.","method":"Biochemical screen for MURR1-associated factors, co-immunoprecipitation, chromatin immunoprecipitation, NF-κB reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP showing chromatin-level NF-κB effect, Co-IP for complex formation, multiple orthogonal methods, foundational family characterization paper","pmids":["15799966"],"is_preprint":false},{"year":2006,"finding":"The solution structure of the N-terminal domain of COMMD1 (residues 1–108) was determined by NMR; it adopts a compact alpha-helical fold with no resemblance to other known helical proteins, and complementary electrostatic surfaces suggest protein-protein interactions occur via this domain.","method":"NMR solution structure determination","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure, single study with rigorous structural characterization","pmids":["17097678"],"is_preprint":false},{"year":2007,"finding":"COMMD1 specifically interacts with the amino-terminal region of ATP7B independent of copper levels or ATOX1; four Wilson disease patient-derived mutations in this region significantly increased ATP7B binding to COMMD1, and COMMD1 markedly decreased the stability of newly synthesized ATP7B via proteasomal degradation.","method":"GST pulldown, co-immunoprecipitation, site-directed mutagenesis, biosynthetic labeling, immunofluorescence microscopy","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (pulldown, Co-IP, mutagenesis, biosynthetic labeling), interaction domain mapped, disease-relevant mutations tested","pmids":["17919502"],"is_preprint":false},{"year":2007,"finding":"COMMD1 directly binds copper as Cu(II) with 1:1 stoichiometry via residues His101, His134, and Met110 in the exon-2-encoded region; it does not bind other divalent metals, identifying it as a Cu(II)-specific binding protein.","method":"EPR spectroscopy, UV-visible absorption, intrinsic fluorescence spectroscopy, DEPC modification of histidines, MALDI MS mapping, site-directed mutagenesis of full-length protein","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple biophysical methods (EPR, UV-vis, fluorescence), chemical modification, mass spectrometry, mutagenesis; Cu(II) binding stoichiometry and residues identified","pmids":["17309234"],"is_preprint":false},{"year":2007,"finding":"Commd1 knockout mice die in utero between 9.5 and 10.5 dpc with placenta vascularization defects; Commd1-deficient embryos show transcriptional upregulation of HIF-1 target genes associated with increased Hif-1α stability, and COMMD1 physically associates with HIF-1α and inhibits HIF-1α stability and HIF-1 transactivation in vitro.","method":"Homozygous Commd1 knockout mouse generation, microarray analysis, co-immunoprecipitation, HIF-1 reporter assay, protein stability assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined molecular phenotype, in vitro mechanistic follow-up with Co-IP and stability assays, multiple orthogonal methods","pmids":["17371845"],"is_preprint":false},{"year":2008,"finding":"COMMD1 localizes to vesicles of the endocytic pathway (not trans-Golgi network or lysosomes) and specifically binds phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) via its C-terminal domain to mediate membrane recruitment; endogenous COMMD1 forms large oligomeric complexes both in cytosol and at membranes, with PtdIns(4,5)P2 interaction increasing oligomer stability.","method":"Co-localization with organelle markers, cell fractionation, lipid-spotted arrays, liposome binding assays, native PAGE, molecular modeling, proteolytic sensitivity","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (lipid arrays, liposome binding, fractionation, co-localization), domain mapping, functional characterization of oligomerization","pmids":["18940794"],"is_preprint":false},{"year":2008,"finding":"Copper-induced translocation of ATP7B is independent of MURR1/COMMD1: COMMD1 does not co-localize with ATP7B during trafficking and siRNA depletion of COMMD1 does not impair ATP7B translocation, indicating COMMD1 acts at a later step in copper excretion rather than in the initial translocation of ATP7B.","method":"Confocal microscopy, RNA interference, siRNA depletion, dominant-negative Rab7 mutant","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — negative result established by two methods (confocal co-localization and siRNA), single lab; mechanistically informative negative finding","pmids":["18974300"],"is_preprint":false},{"year":2009,"finding":"TNF-induced phosphorylation of NF-κB p65 at Ser468 allows binding of COMMD1 and Cullin 2 as components of a multimeric ubiquitin ligase complex mediating p65 ubiquitination and proteasomal degradation; mutation of p65 at Ser468 prevents p65 ubiquitination and degradation, and ChIP experiments show selective recruitment of Ser468-phosphorylated p65 and COMMD1 to the Icam1 promoter.","method":"Site-directed mutagenesis, co-immunoprecipitation, chromatin immunoprecipitation, ubiquitination assays, proteasome inhibition","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — phospho-specific mutagenesis, ChIP, Co-IP, ubiquitination assay; multiple orthogonal methods defining a phosphorylation/ubiquitination switch","pmids":["19270718"],"is_preprint":false},{"year":2009,"finding":"HSCARG associates with COMMD1 (via yeast two-hybrid and Co-IP) and negatively regulates it by accelerating COMMD1 ubiquitination and proteasome-dependent degradation in the cytoplasm; under redox changes HSCARG translocates to the nucleus to promote ubiquitination and degradation of RelA, while cytoplasmic COMMD1 levels are restored.","method":"Yeast two-hybrid screen, co-immunoprecipitation, ubiquitination assays, proteasome inhibition, cellular redox manipulation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — yeast two-hybrid plus Co-IP, ubiquitination assays, single lab with two orthogonal methods","pmids":["19433587"],"is_preprint":false},{"year":2009,"finding":"COMMD1 expression is controlled by its interaction with XIAP; the COMM domain of COMMD1 is required for XIAP binding, specifically two conserved leucine repeats within the COMM domain; a COMMD1 mutant unable to bind XIAP shows complete loss of basal ubiquitination and greatly stabilized protein levels.","method":"Co-immunoprecipitation, site-directed mutagenesis (leucine repeat mutations), ubiquitination assays, protein stability assays","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain mapping by mutagenesis, Co-IP, ubiquitination and stability assays; multiple orthogonal methods in single study","pmids":["18795889"],"is_preprint":false},{"year":2009,"finding":"COMMD1 promotes pVHL- and O2-independent degradation of HIF-1α by competing with chaperone HSP90β for binding to the NH2-terminal DNA-binding and heterodimerization domain of HIF-1α; inhibition of HSP90 activity increased COMMD1-mediated HIF-1α degradation independent of ubiquitin and pVHL, with HSP70 also involved.","method":"Co-immunoprecipitation, competition binding assay, HSP90 inhibitor (17-AAG) treatment, protein stability assays, ubiquitin-independent degradation assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP competition assay, pharmacological inhibitor, stability assays; single lab, domain interaction defined","pmids":["19802386"],"is_preprint":false},{"year":2010,"finding":"COMMD1 inhibits HIF-mediated gene expression by binding directly to the amino terminus of HIF-1α, preventing its dimerization with HIF-1β and subsequent DNA binding and transcriptional activation; repression of COMMD1 in human cell lines increased tumor invasion in a chick xenograft model.","method":"Co-immunoprecipitation, dimerization assays, luciferase reporter assay, chick xenograft model, mouse melanoma lung metastasis model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding to HIF-1α demonstrated, dimerization inhibition shown mechanistically, validated in multiple in vivo models","pmids":["20458141"],"is_preprint":false},{"year":2010,"finding":"Stress-induced nucleolar translocation of RelA requires ubiquitination of RelA, and COMMD1 is the rate-limiting component of the RelA ubiquitin ligase complex; overexpression of COMMD1 promotes stress-mediated nucleolar targeting of RelA, while knockdown blocks this effect and causes RelA to remain in the nucleoplasm. The RelA nucleolar localization signal (aa 27–30) is critical for ubiquitination.","method":"Overexpression and siRNA knockdown, immunofluorescence/nucleolar fractionation, ubiquitination assays, domain deletion analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — gain- and loss-of-function experiments with clear subcellular phenotype, domain mapping, single lab with two orthogonal approaches","pmids":["20048074"],"is_preprint":false},{"year":2010,"finding":"COMMD1 inhibits amiloride-sensitive current in mammalian epithelial cells via its COMM domain; COMMD1 increases ubiquitin modification of ENaC and decreases ENaC cell surface expression; COMMD1 interacts with SGK1 and Akt1, and its effects require Nedd4-2 (dominant-negative Nedd4-2 abolishes COMMD1 effects).","method":"Amiloride-sensitive current measurements in mammalian epithelial cells, surface biotinylation, co-immunoprecipitation, siRNA knockdown, dominant-negative constructs, ENaC PY-motif mutation","journal":"American journal of physiology. Renal physiology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — electrophysiology, surface biotinylation, Co-IP, multiple loss-of-function approaches, domain mapping; mechanistic pathway (Nedd4-2 dependency) established","pmids":["20237237"],"is_preprint":false},{"year":2010,"finding":"Secretory clusterin (sCLU) acts as a ubiquitin-binding protein that enhances COMMD1 and IκB proteasomal degradation by interacting with SCF-βTrCP E3 ligase family members, thereby increasing NF-κB nuclear translocation; knockdown of sCLU stabilizes COMMD1 and IκB, sequestering NF-κB in the cytoplasm.","method":"Co-immunoprecipitation, proteasome inhibitor assays, siRNA knockdown, NF-κB reporter assay, microarray profiling","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, siRNA knockdown, reporter assay; single lab, mechanistic interaction identified","pmids":["20068069"],"is_preprint":false},{"year":2010,"finding":"COMMD1 interacts with SOD1 in a manner that requires CCS-mediated copper incorporation into SOD1; COMMD1 reduces the level of SOD1 homodimers without affecting disulfide oxidation; RNAi knockdown of COMMD1 significantly increases SOD1 activity and decreases superoxide concentrations, while overexpression has the opposite effect.","method":"Co-immunoprecipitation, SOD1 activity assay, RNAi knockdown and overexpression, superoxide measurement, dimerization assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, enzymatic activity assay, gain- and loss-of-function; single lab with multiple orthogonal methods","pmids":["20595380"],"is_preprint":false},{"year":2011,"finding":"Liver-specific Commd1 knockout mice (Commd1^Δhep) develop hepatic copper accumulation (up to 20-fold on copper-enriched diet), providing the first genetic evidence for COMMD1's essential role in hepatic copper homeostasis in vivo.","method":"Liver-specific conditional knockout mice, biochemical and histological copper analyses, gene expression analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific genetic knockout with quantitative copper phenotype, in vivo model","pmids":["22216203"],"is_preprint":false},{"year":2011,"finding":"COMMD1 and clusterin independently regulate degradation of both ATP7A and ATP7B: COMMD1 facilitates ATP7B degradation via the proteasomal pathway while clusterin uses the lysosomal pathway; both proteins interact with ATP7B independently and non-competitively, and endogenous ATP7B exists in a complex containing both.","method":"Co-immunoprecipitation, overexpression and knockdown, pathway-specific inhibitors (proteasome vs lysosome), endogenous complex analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — pathway-specific inhibitors define distinct degradation routes, Co-IP, gain- and loss-of-function, multiple orthogonal methods","pmids":["22130675"],"is_preprint":false},{"year":2011,"finding":"COMMD1 regulates Cullin RING Ligases (CRLs) by antagonizing CAND1 binding: COMMD1 interacts with multiple Cullins, the COMMD1-Cul2 complex cannot bind CAND1, and COMMD1 can actively displace CAND1 from CRLs, promoting CRL activation.","method":"Co-immunoprecipitation, competitive binding assay, CAND1 displacement assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and competition binding assay, single lab, mechanistic displacement shown","pmids":["21778237"],"is_preprint":false},{"year":2011,"finding":"COMMD1 interacts with CFTR endogenously, promotes CFTR cell surface expression by protecting CFTR from ubiquitination, sustaining CFTR at the plasma membrane.","method":"Genetic screen, co-immunoprecipitation in cells with endogenous expression, surface biotinylation, ubiquitination assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — endogenous Co-IP, surface biotinylation, ubiquitination assay; single lab with multiple methods","pmids":["21483833"],"is_preprint":false},{"year":2011,"finding":"COMMD1 regulates δENaC through its COMM domain; co-expression of COMMD1 reduces δENaC surface expression and increases δENaC ubiquitination; COMMD1 promotes localization of δENaC to early/recycling endosomes.","method":"Co-immunoprecipitation, surface expression assay, ubiquitination assay, immunocytochemistry and confocal microscopy with endosomal markers","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — surface expression, ubiquitination, and localization assays; single lab, COMM domain requirement shown","pmids":["21741370"],"is_preprint":false},{"year":2008,"finding":"Tumor suppressor ARF associates with COMMD1 and promotes non-classic Lys63-mediated polyubiquitination of COMMD1 in a p53-independent manner; this Lys63-linked ubiquitination does not target COMMD1 for proteasomal degradation; ARF redistributes from nucleolus to nucleoplasm upon DNA damage to interact with COMMD1.","method":"Co-immunoprecipitation, ubiquitin chain-specific (K63/K48) analysis, deletion mapping of ARF, actinomycin D DNA damage, proteasome assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ubiquitin chain typing, Co-IP, domain deletion; single lab with multiple approaches","pmids":["18305112"],"is_preprint":false},{"year":2013,"finding":"COMMD1 binds to the C-terminal domain of NKCC1 (aa 1040–1134) via its N-terminus (aa 1–47) in airway epithelial cells and modulates NKCC1 ubiquitination and membrane expression; COMMD1 loss reduces baseline NKCC1 membrane expression and blunts hyperosmolarity-stimulated NKCC1 trafficking.","method":"Yeast two-hybrid, GST pulldown, Co-IP with endogenous proteins, siRNA knockdown, membrane expression assay, ubiquitination assay","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — yeast two-hybrid plus Co-IP plus functional knockdown; interaction domain mapped, single lab","pmids":["23515529"],"is_preprint":false},{"year":2014,"finding":"COMMD1 is directly linked to early endosomes through interaction with the CCC complex (CCDC22/CCDC93/C16orf62); the CCC complex interacts with the WASH complex subunit FAM21 via C-terminal ends of CCDC22 and CCDC93; depletion of CCC complex components prevents copper-dependent movement of ATP7A from endosomes, causing intracellular copper accumulation.","method":"Co-immunoprecipitation, siRNA knockdown, endosomal co-localization, copper accumulation assays, domain mapping","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, siRNA depletion, localization, copper assays; mechanistic pathway defined (CCC-WASH interaction), replicated with multiple CCC components","pmids":["25355947"],"is_preprint":false},{"year":2014,"finding":"p300 acetylates COMMD1, protecting it from XIAP-mediated proteasomal degradation; p300-mediated COMMD1 acetylation is required for COMMD1 to bind RelA under aspirin-mediated stress conditions but not TNF stimulation; this controls stress-specific (but not cytokine-driven) ubiquitination and nucleolar translocation of RelA.","method":"Co-immunoprecipitation, acetylation assays, siRNA knockdown, RelA nucleolar localization assay, stimulus-specific comparison","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — acetylation assay, Co-IP, stimulus-specific functional assays; single lab with multiple approaches","pmids":["25074812"],"is_preprint":false},{"year":2014,"finding":"COMMD1 modulates aggregation of misfolded SOD1 in a client-specific manner: COMMD1 enhances formation of mutant SOD1 (mSOD1) aggregates and co-localizes to mSOD1 inclusion sites, forming high molecular weight complexes; in contrast, COMMD1 decreases abundance of mutant Parkin inclusions and does not affect polyglutamine-expanded Huntingtin aggregation.","method":"Co-immunoprecipitation, co-localization by confocal microscopy, high molecular weight complex analysis, overexpression in cell models of ALS and PD","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-localization, HMW complex analysis, overexpression; single lab, client-specific effects documented with multiple substrates","pmids":["24691167"],"is_preprint":false},{"year":2017,"finding":"DRR1, F-actin, and COMMD1 form a novel nuclear complex; stability of COMMD1 is enhanced within this complex; increased nuclear COMMD1 promotes NF-κB degradation; DRR1 and COMMD1 together suppress cyclin D1 expression, G1/S transition, and cell proliferation in neuroblastoma cells, with the DRR1-F-actin interaction being required.","method":"Co-immunoprecipitation, nuclear fractionation, NF-κB activity assay, cell cycle analysis, proliferation assay, DRR1-actin binding mutants","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP for complex, functional knockdown/overexpression with cell cycle readout; single lab with multiple methods","pmids":["28604741"],"is_preprint":false},{"year":2017,"finding":"COMMD1 in human macrophages restrains RANKL-induced NF-κB signaling and an E2F1-dependent metabolic pathway; hypoxia suppresses COMMD1 protein expression, augmenting RANKL-induced inflammatory and E2F1 target gene expression and osteoclastogenesis; myeloid-specific Commd1 deletion in mice increased osteoclastogenesis in arthritis and inflammatory osteolysis models.","method":"Myeloid-specific conditional knockout mice, RANKL stimulation, NF-κB reporter assays, E2F1 target gene analysis, arthritis and osteolysis mouse models, eQTL analysis","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with defined molecular pathway (NF-κB and E2F1-metabolic), multiple in vivo disease models, eQTL validation","pmids":["28723554"],"is_preprint":false},{"year":2019,"finding":"COMMD1 modulates copper-responsive ATP7B trafficking through recruitment to PtdIns(4,5)P2; decreased COMMD1 results in loss of ATP7B from lysosomes and trans-Golgi network under high copper; overexpression of a COMMD1 mutant deficient in PtdIns(4,5)P2 binding has little impact on ATP7B trafficking, demonstrating a PtdIns(4,5)P2-dependent mechanism.","method":"Quantitative colocalization analysis, COMMD1 PtdIns(4,5)P2-binding mutant, siRNA knockdown, copper export assay, organelle markers","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — mutant analysis plus co-localization, single lab with domain-specific mutation establishing PtdIns(4,5)P2 dependency","pmids":["31515276"],"is_preprint":false},{"year":2021,"finding":"COMMD1 is required for efficient repair of DNA double strand breaks and functions in both non-homologous end joining (NHEJ) and homologous recombination (HR) pathways, as determined by DSB reporter assays in COMMD1-siRNA-depleted cells.","method":"siRNA depletion, DSB repair reporter assays for NHEJ and HR, cell viability and cell cycle assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional DSB reporter assays with siRNA knockdown; single lab, two reporter systems","pmids":["33669398"],"is_preprint":false},{"year":2014,"finding":"COMMD1 reinforces HIV-1 latency in myeloid cells through IκB-α stabilization: COMMD1 induction in latently HIV-1-infected myeloid cells (via PI3K-JAK pathway) inhibits proteasomal degradation of IκB-α by increasing COMMD1-IκB-α interaction, attenuating NF-κB signaling during innate immune stimulation.","method":"Four pairs of latently HIV-1-infected and parental cells, Western blot, Co-IP, siRNA knockdown, PI3K-JAK pathway inhibitors","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP for COMMD1-IκB-α interaction, pharmacological pathway dissection, multiple cell line pairs; single lab","pmids":["25520503"],"is_preprint":false},{"year":2024,"finding":"An ATP7B splicing mutation (c.1543+1G>C) causes skipping of exon 3, producing mutant ATP7B with altered N-terminus that shows enhanced interaction with COMMD1 and is consequently degraded via the ubiquitin-proteasome pathway; this enhanced COMMD1 binding represents a universal pathogenic mechanism for ATP7B variants with altered N-terminus.","method":"Splicing assay, RNA pulldown, ATP7B-knockout HuH-7 cells, Atp7b-/- mice, co-immunoprecipitation, ubiquitin-proteasome pathway assay, intracellular copper measurement","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (splicing assay, Co-IP, KO cell and animal models), mechanistic pathway defined, single lab","pmids":["39389536"],"is_preprint":false},{"year":2025,"finding":"COMMD1 knockdown in ALS models enhances palmitoylation of the copper chaperone CCS via activation of the HIF-1α/FASN signaling axis, facilitating CCS membrane translocation and promoting copper loading into SOD1; in vivo, COMMD1 deficiency in hSOD1G93A transgenic mice ameliorates motor function deterioration and prolongs survival.","method":"siRNA knockdown, palmitoylation assay, membrane fractionation, HIF-1α/FASN pathway analysis, transgenic mouse model (hSOD1G93A), behavioral/survival assays","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway (HIF-1α/FASN-CCS palmitoylation) identified with multiple assays plus in vivo model; single lab","pmids":["42156174"],"is_preprint":false},{"year":2025,"finding":"Crystal and cryo-EM structures of bacterial and archaeal COMMD-like proteins reveal homooligomeric ring assemblies of 8 or 10 subunits built from core dimeric building blocks with inter-dimer interactions analogous to the eukaryotic heterodecameric Commander complex COMMD ring; phylogenetic analysis indicates the closest relatives to eukaryotic COMMD proteins are found in Myxococcota bacteria.","method":"Cryo-EM structure determination, crystal structure determination, biophysical characterization, phylogenetic analysis (sequence + FoldSeek 3Di structural alphabet)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — high-quality structural methods (cryo-EM, crystal structure) but preprint, not peer-reviewed; establishes prokaryotic structural homologs","pmids":["bio_10.1101_2025.09.01.673571"],"is_preprint":true}],"current_model":"COMMD1 is a multifunctional scaffold protein that localizes to endosomal membranes via PtdIns(4,5)P2 binding and functions as part of the CCC-WASH complex to regulate endosomal trafficking of copper transporters (ATP7A, ATP7B); it promotes ubiquitin-proteasome-dependent degradation of multiple substrates including NF-κB RelA (via a Ser468-phosphorylation-dependent E3 ligase complex with Cullin 2), HIF-1α (by competing with HSP90β and preventing HIF-1α/HIF-1β dimerization), and misfolded copper transporters; its own stability is controlled by XIAP-mediated K48-polyubiquitination (degrading it) and p300-mediated acetylation (stabilizing it), and it directly binds Cu(II) with 1:1 stoichiometry via His101, His134, and Met110 in its exon-2-encoded region."},"narrative":{"mechanistic_narrative":"COMMD1 (originally MURR1) is a copper-binding scaffold protein that couples copper homeostasis to endosomal protein trafficking and ubiquitin-proteasome-dependent degradation of multiple membrane and signaling substrates [PMID:12968035, PMID:17309234, PMID:25355947]. It binds Cu(II) with 1:1 stoichiometry through His101, His134, and Met110 in its exon-2-encoded region [PMID:17309234] and is recruited to endocytic-pathway vesicles by binding PtdIns(4,5)P2 through its C-terminal domain, where it forms large oligomeric complexes [PMID:18940794]. Through the conserved COMM domain it engages homo- and heteromeric partners [PMID:15799966], and it directly links to early endosomes via the CCC complex (CCDC22/CCDC93/C16orf62), which connects to the WASH-complex subunit FAM21 to drive copper-dependent endosomal movement of ATP7A; loss of CCC components causes intracellular copper accumulation [PMID:25355947]. COMMD1 binds the copper-binding amino terminus of the Wilson disease protein ATP7B [PMID:12968035, PMID:17919502] and a PtdIns(4,5)P2-dependent mechanism governs copper-responsive ATP7B trafficking [PMID:31515276]; it promotes proteasomal degradation of newly synthesized ATP7B, with disease-associated N-terminal mutations enhancing COMMD1 binding and accelerating degradation [PMID:17919502, PMID:39389536]. Liver-specific Commd1 deletion produces marked hepatic copper accumulation, establishing an essential in vivo role in copper homeostasis [PMID:22216203]. In parallel, COMMD1 negatively regulates NF-κB: it acts at the chromatin level on NF-κB association [PMID:15799966], and TNF-induced Ser468 phosphorylation of RelA/p65 recruits COMMD1 and Cullin 2 into a multimeric ubiquitin ligase that targets p65 for degradation and stress-induced nucleolar translocation [PMID:19270718, PMID:20048074]. COMMD1 also represses HIF signaling by binding the amino terminus of HIF-1α, competing with HSP90β and blocking HIF-1α/HIF-1β dimerization and transactivation [PMID:19802386, PMID:20458141]; Commd1-null embryos die with placental vascularization defects and elevated HIF-1α [PMID:17371845]. Its own abundance is set by competing post-translational marks: XIAP binds the COMM domain and catalyzes K48-linked polyubiquitination driving degradation [PMID:14685266, PMID:18795889], while p300-mediated acetylation stabilizes it [PMID:25074812]. More broadly, COMMD1 controls ubiquitination, surface expression, and trafficking of multiple ion channels and transporters including ENaC, CFTR, and NKCC1 [PMID:14645214, PMID:20237237, PMID:21483833, PMID:23515529], and antagonizes CAND1 to activate Cullin-RING ligases [PMID:21778237].","teleology":[{"year":2003,"claim":"Established COMMD1/MURR1 as a negative regulator of NF-κB, defining its first signaling function via control of IκB-α stability.","evidence":"RNAi knockdown in primary resting CD4+ T cells with proteasome inhibition and NF-κB reporters","pmids":["14685242"],"confidence":"High","gaps":["Did not define the direct molecular target or whether the effect was cytoplasmic versus nuclear","Mechanism of IκB-α stabilization left unresolved"]},{"year":2003,"claim":"Connected COMMD1 to copper biology by demonstrating direct interaction with the Wilson disease transporter ATP7B and opposing regulation by the ubiquitin ligase XIAP.","evidence":"In vitro binding and Co-IP for ATP7B; reciprocal Co-IP, K48 ubiquitin chain typing, Xiap-knockout mice and copper measurements","pmids":["12968035","14685266"],"confidence":"High","gaps":["Did not establish where in the copper-excretion pathway COMMD1 acts","Did not resolve whether COMMD1 affects ATP7B trafficking or stability"]},{"year":2003,"claim":"Extended COMMD1's substrate range to ion channels by showing it inhibits ENaC-mediated sodium current, hinting at a general role in transporter regulation.","evidence":"Yeast two-hybrid, GST pulldown, Co-IP, and Xenopus oocyte electrophysiology with domain deletion","pmids":["14645214"],"confidence":"High","gaps":["Mechanism of channel inhibition not defined","Performed in heterologous oocyte system rather than native epithelium"]},{"year":2005,"claim":"Defined COMMD1 as the founding member of the COMM-domain family and localized its NF-κB effect to chromatin association rather than nuclear import.","evidence":"Biochemical interaction screen, Co-IP for complex formation, and ChIP","pmids":["15799966"],"confidence":"High","gaps":["Did not identify the ligase converting chromatin binding to p65 turnover","Functional consequences of homo/heteromeric COMMD complexes unresolved"]},{"year":2006,"claim":"Provided the first structural view of COMMD1, showing a novel alpha-helical N-terminal fold with surfaces suited to protein interactions.","evidence":"NMR solution structure of residues 1–108","pmids":["17097678"],"confidence":"High","gaps":["Structure of the COMM domain and full-length protein not determined","No partner-bound structure to define interaction interfaces"]},{"year":2007,"claim":"Identified COMMD1 as a copper(II)-specific binding protein and clarified its role in ATP7B degradation, linking metal binding to substrate stability.","evidence":"EPR, UV-vis, fluorescence, DEPC modification, MS mapping, and mutagenesis for Cu(II) binding; GST pulldown, Co-IP, mutagenesis, and biosynthetic labeling for ATP7B","pmids":["17309234","17919502"],"confidence":"High","gaps":["Did not link copper binding mechanistically to ATP7B degradation or trafficking","Did not identify the E3 ligase degrading ATP7B"]},{"year":2007,"claim":"Demonstrated an essential developmental role and a HIF-1α-regulatory function, broadening COMMD1 beyond NF-κB and copper.","evidence":"Commd1 knockout mice, microarray, Co-IP, HIF-1 reporter and protein stability assays","pmids":["17371845"],"confidence":"High","gaps":["Mechanism of HIF-1α destabilization not defined","Embryonic lethality precluded analysis of adult phenotypes"]},{"year":2008,"claim":"Established the membrane-recruitment basis of COMMD1 function by identifying PtdIns(4,5)P2 binding through the C-terminus and endosomal localization with oligomerization.","evidence":"Co-localization, fractionation, lipid arrays, liposome binding, native PAGE, and modeling","pmids":["18940794"],"confidence":"High","gaps":["Did not connect lipid binding to a specific trafficking step","Stoichiometry and composition of the oligomers unresolved"]},{"year":2008,"claim":"Refined the regulation of COMMD1 stability, showing ARF promotes non-degradative K63 ubiquitination distinct from XIAP's degradative K48 marks.","evidence":"Co-IP, K63/K48 chain typing, ARF deletion mapping, DNA damage induction","pmids":["18305112"],"confidence":"Medium","gaps":["Functional consequence of K63 ubiquitination on COMMD1 activity not defined","Single lab, ubiquitin chain typing not orthogonally confirmed"]},{"year":2009,"claim":"Defined a phosphorylation-gated ubiquitin ligase mechanism: Ser468-phosphorylated p65 recruits COMMD1 and Cullin 2 to drive p65 ubiquitination and degradation at target promoters.","evidence":"Phospho-specific mutagenesis, Co-IP, ChIP, ubiquitination assays, proteasome inhibition","pmids":["19270718"],"confidence":"High","gaps":["Full subunit composition and substrate specificity of the ligase not enumerated","Did not establish promoter selectivity rules"]},{"year":2009,"claim":"Identified upstream regulators and additional pathways controlling COMMD1 levels and HIF repression, including HSCARG-driven degradation and HSP90-competitive HIF-1α destabilization.","evidence":"Yeast two-hybrid, Co-IP, ubiquitination and redox assays (HSCARG); Co-IP competition, 17-AAG, ubiquitin-independent stability assays (HIF-1α/HSP90β)","pmids":["19433587","19802386"],"confidence":"Medium","gaps":["HSCARG-COMMD1 ligase identity not defined","Ubiquitin-independent HIF-1α degradation route mechanistically incomplete"]},{"year":2010,"claim":"Consolidated mechanism across NF-κB, HIF, ENaC, and SOD1: COMMD1 blocks HIF-1α/HIF-1β dimerization, drives stress-induced RelA nucleolar targeting, regulates ENaC via Nedd4-2, and limits SOD1 activity.","evidence":"Co-IP, dimerization/luciferase assays and xenograft/metastasis models (HIF); nucleolar fractionation and ubiquitination (RelA); electrophysiology, biotinylation, Co-IP, dominant-negative Nedd4-2 (ENaC); SOD1 activity and dimerization assays","pmids":["20458141","20048074","20237237","20595380","20068069"],"confidence":"High","gaps":["Whether a single COMMD1 complex serves all substrates is unresolved","SOD1 and clusterin links rest on single-lab data"]},{"year":2011,"claim":"Provided genetic proof of COMMD1's hepatic copper role and broadened its transporter clientele while defining its action on Cullin-RING ligases via CAND1 antagonism.","evidence":"Liver-specific conditional knockout with copper analyses; Co-IP and pathway-specific inhibitors (ATP7A/ATP7B, clusterin); endogenous Co-IP and biotinylation (CFTR, δENaC); CAND1 displacement assays","pmids":["22216203","22130675","21483833","21741370","21778237"],"confidence":"High","gaps":["Mechanistic basis for substrate-specific degradation route choice unclear","CRL regulation not linked to a defined cellular output"]},{"year":2014,"claim":"Anchored COMMD1 in the CCC-WASH endosomal trafficking machinery and clarified acetylation-controlled stability and stimulus-specific NF-κB regulation.","evidence":"Co-IP, siRNA, endosomal co-localization and copper assays (CCC/WASH); acetylation assays and stimulus-specific RelA assays (p300)","pmids":["25355947","25074812"],"confidence":"High","gaps":["How COMMD1 selects copper-transporter cargo within the CCC complex remains undefined","Acetylation site and its interplay with XIAP ubiquitination not fully mapped"]},{"year":2017,"claim":"Linked COMMD1 to physiological inflammatory and proliferative control in vivo through macrophage NF-κB/E2F1 regulation and a nuclear DRR1-actin complex.","evidence":"Myeloid-specific knockout mice with arthritis/osteolysis models and eQTL (macrophages); Co-IP, nuclear fractionation, cell-cycle assays (DRR1)","pmids":["28723554","28604741"],"confidence":"High","gaps":["Mechanistic connection between copper trafficking and inflammatory phenotypes not established","DRR1 complex function rests on single-lab data"]},{"year":2024,"claim":"Extended the ATP7B-degradation paradigm to a clinical mechanism, showing N-terminus-altering variants gain enhanced COMMD1 binding and accelerated proteasomal turnover.","evidence":"Splicing assay, RNA pulldown, ATP7B-knockout cells, Atp7b-/- mice, Co-IP, ubiquitin-proteasome and copper assays","pmids":["39389536"],"confidence":"Medium","gaps":["Generalizability across all N-terminal variants relies on a single representative mutation","Single-lab confirmation"]},{"year":2025,"claim":"Implicated COMMD1 in genome maintenance and copper-dependent SOD1 disease pathways, including a HIF-1α/FASN-CCS palmitoylation axis in ALS models.","evidence":"DSB reporter assays with siRNA (NHEJ/HR); palmitoylation, fractionation, pathway analysis and hSOD1G93A mice (CCS axis)","pmids":["33669398","42156174"],"confidence":"Medium","gaps":["Direct molecular role of COMMD1 in DSB repair not defined","Connection between DNA repair and copper/trafficking functions unknown"]},{"year":null,"claim":"How a single PtdIns(4,5)P2- and copper-binding scaffold integrates endosomal trafficking, multi-substrate ubiquitination, transcription-factor degradation, and DNA repair into one mechanistic logic remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of substrate selection within the Commander/CCC assembly","Whether copper binding directly gates COMMD1's signaling functions is untested","Physiological hierarchy among COMMD1's NF-κB, HIF, copper, and DNA-repair roles is undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,28,12]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[10,33]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[16,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[12,23,1]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[10,28,25]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[4,10]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,17,31]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[28,33,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12,0,16]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[2,21,28]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[12,7,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,32]}],"complexes":["CCC complex (COMMD1/CCDC22/CCDC93/C16orf62)","COMMD1-Cullin 2 ubiquitin ligase","DRR1-F-actin-COMMD1 nuclear complex"],"partners":["ATP7B","XIAP","RELA","HIF1A","CCDC22","CUL2","CFTR","NKCC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N668","full_name":"COMM domain-containing protein 1","aliases":["Protein Murr1"],"length_aa":190,"mass_kda":21.2,"function":"Scaffold protein in the commander complex that is essential for endosomal recycling of transmembrane cargos; the commander complex is composed of the CCC subcomplex and the retriever subcomplex (PubMed:37172566, PubMed:38459129). Can modulate activity of cullin-RING E3 ubiquitin ligase (CRL) complexes by displacing CAND1; in vitro promotes CRL E3 activity and dissociates CAND1 from CUL1 and CUL2 (PubMed:21778237). Promotes ubiquitination of NF-kappa-B subunit RELA and its subsequent proteasomal degradation. Down-regulates NF-kappa-B activity (PubMed:15799966, PubMed:17183367, PubMed:20048074). Involved in the regulation of membrane expression and ubiquitination of SLC12A2 (PubMed:23515529). Modulates Na(+) transport in epithelial cells by regulation of apical cell surface expression of amiloride-sensitive sodium channel (ENaC) subunits and by promoting their ubiquitination presumably involving NEDD4L. Promotes the localization of SCNN1D to recycling endosomes (PubMed:14645214, PubMed:20237237, PubMed:21741370). Promotes CFTR cell surface expression through regulation of its ubiquitination (PubMed:21483833). Down-regulates SOD1 activity by interfering with its homodimerization (PubMed:20595380). Plays a role in copper ion homeostasis. Involved in copper-dependent ATP7A trafficking between the trans-Golgi network and vesicles in the cell periphery; the function is proposed to depend on its association within the CCC complex and cooperation with the WASH complex on early endosomes (PubMed:25355947). Can bind one copper ion per monomer (PubMed:17309234). May function to facilitate biliary copper excretion within hepatocytes. Binds to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) (PubMed:18940794). Involved in the regulation of HIF1A-mediated transcription; competes with ARNT/Hif-1-beta for binding to HIF1A resulting in decreased DNA binding and impaired transcriptional activation by HIF-1 (PubMed:20458141). Negatively regulates neuroblastoma G1/S phase cell cycle progression and cell proliferation by stimulating ubiquitination of NF-kappa-B subunit RELA and NF-kappa-B degradation in a FAM107A- and actin-dependent manner (PubMed:28604741)","subcellular_location":"Nucleus; Cytoplasm; Endosome membrane; Cytoplasmic vesicle; Early endosome; Recycling endosome","url":"https://www.uniprot.org/uniprotkb/Q8N668/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/COMMD1","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000173163","cell_line_id":"CID000266","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"cytoplasmic","grade":1}],"interactors":[{"gene":"CCDC22","stoichiometry":10.0},{"gene":"CCDC93","stoichiometry":10.0},{"gene":"C16ORF62","stoichiometry":10.0},{"gene":"COMMD6","stoichiometry":10.0},{"gene":"FAM45A;FAM45B","stoichiometry":10.0},{"gene":"COMMD2","stoichiometry":10.0},{"gene":"COMMD9","stoichiometry":10.0},{"gene":"ARGLU1","stoichiometry":10.0},{"gene":"COMMD8","stoichiometry":10.0},{"gene":"COMMD3-BMI1;COMMD3;BMI1","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000266","total_profiled":1310},"omim":[{"mim_id":"620553","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 93; CCDC93","url":"https://www.omim.org/entry/620553"},{"mim_id":"620004","title":"NMRA-LIKE REDOX SENSOR 1; NMRAL1","url":"https://www.omim.org/entry/620004"},{"mim_id":"616704","title":"COMM DOMAIN-CONTAINING PROTEIN 10; COMMD10","url":"https://www.omim.org/entry/616704"},{"mim_id":"616703","title":"COMM DOMAIN-CONTAINING PROTEIN 7; COMMD7","url":"https://www.omim.org/entry/616703"},{"mim_id":"616701","title":"COMM DOMAIN-CONTAINING PROTEIN 4; COMMD4","url":"https://www.omim.org/entry/616701"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/COMMD1"},"hgnc":{"alias_symbol":["MURR1","MGC27155"],"prev_symbol":["C2orf5"]},"alphafold":{"accession":"Q8N668","domains":[{"cath_id":"-","chopping":"10-114","consensus_level":"high","plddt":90.1881,"start":10,"end":114},{"cath_id":"3.10.450,3.10.450","chopping":"118-132_140-188","consensus_level":"medium","plddt":88.005,"start":118,"end":188}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N668","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N668-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N668-F1-predicted_aligned_error_v6.png","plddt_mean":86.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=COMMD1","jax_strain_url":"https://www.jax.org/strain/search?query=COMMD1"},"sequence":{"accession":"Q8N668","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N668.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N668/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N668"}},"corpus_meta":[{"pmid":"15799966","id":"PMC_15799966","title":"COMMD 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lymphocytes.\",\n      \"method\": \"RNA interference knockdown in primary resting CD4+ T cells, proteasome inhibitor assays, NF-κB reporter assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi knockdown with defined molecular phenotype (IκB-α stabilization, NF-κB activity, HIV replication), replicated across multiple experimental systems in a high-impact journal\",\n      \"pmids\": [\"14685242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"XIAP interacts with MURR1/COMMD1 and acts as its ubiquitin ligase, forming K48-linked polyubiquitin chains on MURR1 that promote its proteasomal degradation; XIAP-deficient mice had reduced copper levels while MURR1 suppression increased intracellular copper, indicating XIAP and MURR1 have opposing effects on copper homeostasis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitin chain analysis, Xiap-knockout mouse tissues, copper measurements in cells and tissues\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitin chain typing (K48), genetic knockout model, replicated across cell and animal systems\",\n      \"pmids\": [\"14685266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MURR1/COMMD1 directly interacts with the Wilson disease protein ATP7B in vitro and in vivo; this interaction is mediated via the copper-binding amino terminus of ATP7B and is specific for this copper transporter, placing MURR1 in the pathway of hepatic biliary copper excretion.\",\n      \"method\": \"In vitro binding assay, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstitution plus in vivo Co-IP, interaction domain mapped, replicated by multiple subsequent studies\",\n      \"pmids\": [\"12968035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MURR1/COMMD1 interacts with delta, beta, and gamma subunits of the epithelial sodium channel (ENaC) and inhibits amiloride-sensitive sodium current in a dose-dependent manner when co-expressed in Xenopus oocytes; deletion of the last 59 amino acids of deltaENaC abolished inhibition.\",\n      \"method\": \"Yeast two-hybrid screen, GST pulldown, co-immunoprecipitation, Xenopus oocyte electrophysiology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — electrophysiology (functional readout), pulldown, Co-IP, domain deletion mapping in single study with multiple orthogonal methods\",\n      \"pmids\": [\"14645214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MURR1/COMMD1 protein is absent in livers of copper toxicosis-affected Bedlington terriers; in cells the protein localizes to cytosol and membrane fractions and is associated with a vesicular compartment, suggesting a role in vesicular copper sequestration.\",\n      \"method\": \"Western blot with polyclonal antibodies, indirect immunofluorescence, cell fractionation\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct localization experiment by fractionation and immunofluorescence, single lab, two methods\",\n      \"pmids\": [\"14568250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"COMMD proteins form a novel family defined by the conserved COMM domain, which functions as an interface for protein-protein interactions including homo- and heteromeric complex formation. COMMD1 (MURR1) suppresses NF-κB not by affecting nuclear translocation or DNA binding but by acting in the nucleus to affect NF-κB association with chromatin.\",\n      \"method\": \"Biochemical screen for MURR1-associated factors, co-immunoprecipitation, chromatin immunoprecipitation, NF-κB reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP showing chromatin-level NF-κB effect, Co-IP for complex formation, multiple orthogonal methods, foundational family characterization paper\",\n      \"pmids\": [\"15799966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The solution structure of the N-terminal domain of COMMD1 (residues 1–108) was determined by NMR; it adopts a compact alpha-helical fold with no resemblance to other known helical proteins, and complementary electrostatic surfaces suggest protein-protein interactions occur via this domain.\",\n      \"method\": \"NMR solution structure determination\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure, single study with rigorous structural characterization\",\n      \"pmids\": [\"17097678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"COMMD1 specifically interacts with the amino-terminal region of ATP7B independent of copper levels or ATOX1; four Wilson disease patient-derived mutations in this region significantly increased ATP7B binding to COMMD1, and COMMD1 markedly decreased the stability of newly synthesized ATP7B via proteasomal degradation.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation, site-directed mutagenesis, biosynthetic labeling, immunofluorescence microscopy\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (pulldown, Co-IP, mutagenesis, biosynthetic labeling), interaction domain mapped, disease-relevant mutations tested\",\n      \"pmids\": [\"17919502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"COMMD1 directly binds copper as Cu(II) with 1:1 stoichiometry via residues His101, His134, and Met110 in the exon-2-encoded region; it does not bind other divalent metals, identifying it as a Cu(II)-specific binding protein.\",\n      \"method\": \"EPR spectroscopy, UV-visible absorption, intrinsic fluorescence spectroscopy, DEPC modification of histidines, MALDI MS mapping, site-directed mutagenesis of full-length protein\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple biophysical methods (EPR, UV-vis, fluorescence), chemical modification, mass spectrometry, mutagenesis; Cu(II) binding stoichiometry and residues identified\",\n      \"pmids\": [\"17309234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Commd1 knockout mice die in utero between 9.5 and 10.5 dpc with placenta vascularization defects; Commd1-deficient embryos show transcriptional upregulation of HIF-1 target genes associated with increased Hif-1α stability, and COMMD1 physically associates with HIF-1α and inhibits HIF-1α stability and HIF-1 transactivation in vitro.\",\n      \"method\": \"Homozygous Commd1 knockout mouse generation, microarray analysis, co-immunoprecipitation, HIF-1 reporter assay, protein stability assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined molecular phenotype, in vitro mechanistic follow-up with Co-IP and stability assays, multiple orthogonal methods\",\n      \"pmids\": [\"17371845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"COMMD1 localizes to vesicles of the endocytic pathway (not trans-Golgi network or lysosomes) and specifically binds phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) via its C-terminal domain to mediate membrane recruitment; endogenous COMMD1 forms large oligomeric complexes both in cytosol and at membranes, with PtdIns(4,5)P2 interaction increasing oligomer stability.\",\n      \"method\": \"Co-localization with organelle markers, cell fractionation, lipid-spotted arrays, liposome binding assays, native PAGE, molecular modeling, proteolytic sensitivity\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (lipid arrays, liposome binding, fractionation, co-localization), domain mapping, functional characterization of oligomerization\",\n      \"pmids\": [\"18940794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Copper-induced translocation of ATP7B is independent of MURR1/COMMD1: COMMD1 does not co-localize with ATP7B during trafficking and siRNA depletion of COMMD1 does not impair ATP7B translocation, indicating COMMD1 acts at a later step in copper excretion rather than in the initial translocation of ATP7B.\",\n      \"method\": \"Confocal microscopy, RNA interference, siRNA depletion, dominant-negative Rab7 mutant\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — negative result established by two methods (confocal co-localization and siRNA), single lab; mechanistically informative negative finding\",\n      \"pmids\": [\"18974300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TNF-induced phosphorylation of NF-κB p65 at Ser468 allows binding of COMMD1 and Cullin 2 as components of a multimeric ubiquitin ligase complex mediating p65 ubiquitination and proteasomal degradation; mutation of p65 at Ser468 prevents p65 ubiquitination and degradation, and ChIP experiments show selective recruitment of Ser468-phosphorylated p65 and COMMD1 to the Icam1 promoter.\",\n      \"method\": \"Site-directed mutagenesis, co-immunoprecipitation, chromatin immunoprecipitation, ubiquitination assays, proteasome inhibition\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — phospho-specific mutagenesis, ChIP, Co-IP, ubiquitination assay; multiple orthogonal methods defining a phosphorylation/ubiquitination switch\",\n      \"pmids\": [\"19270718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"HSCARG associates with COMMD1 (via yeast two-hybrid and Co-IP) and negatively regulates it by accelerating COMMD1 ubiquitination and proteasome-dependent degradation in the cytoplasm; under redox changes HSCARG translocates to the nucleus to promote ubiquitination and degradation of RelA, while cytoplasmic COMMD1 levels are restored.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, ubiquitination assays, proteasome inhibition, cellular redox manipulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — yeast two-hybrid plus Co-IP, ubiquitination assays, single lab with two orthogonal methods\",\n      \"pmids\": [\"19433587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"COMMD1 expression is controlled by its interaction with XIAP; the COMM domain of COMMD1 is required for XIAP binding, specifically two conserved leucine repeats within the COMM domain; a COMMD1 mutant unable to bind XIAP shows complete loss of basal ubiquitination and greatly stabilized protein levels.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (leucine repeat mutations), ubiquitination assays, protein stability assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain mapping by mutagenesis, Co-IP, ubiquitination and stability assays; multiple orthogonal methods in single study\",\n      \"pmids\": [\"18795889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"COMMD1 promotes pVHL- and O2-independent degradation of HIF-1α by competing with chaperone HSP90β for binding to the NH2-terminal DNA-binding and heterodimerization domain of HIF-1α; inhibition of HSP90 activity increased COMMD1-mediated HIF-1α degradation independent of ubiquitin and pVHL, with HSP70 also involved.\",\n      \"method\": \"Co-immunoprecipitation, competition binding assay, HSP90 inhibitor (17-AAG) treatment, protein stability assays, ubiquitin-independent degradation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP competition assay, pharmacological inhibitor, stability assays; single lab, domain interaction defined\",\n      \"pmids\": [\"19802386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"COMMD1 inhibits HIF-mediated gene expression by binding directly to the amino terminus of HIF-1α, preventing its dimerization with HIF-1β and subsequent DNA binding and transcriptional activation; repression of COMMD1 in human cell lines increased tumor invasion in a chick xenograft model.\",\n      \"method\": \"Co-immunoprecipitation, dimerization assays, luciferase reporter assay, chick xenograft model, mouse melanoma lung metastasis model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding to HIF-1α demonstrated, dimerization inhibition shown mechanistically, validated in multiple in vivo models\",\n      \"pmids\": [\"20458141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Stress-induced nucleolar translocation of RelA requires ubiquitination of RelA, and COMMD1 is the rate-limiting component of the RelA ubiquitin ligase complex; overexpression of COMMD1 promotes stress-mediated nucleolar targeting of RelA, while knockdown blocks this effect and causes RelA to remain in the nucleoplasm. The RelA nucleolar localization signal (aa 27–30) is critical for ubiquitination.\",\n      \"method\": \"Overexpression and siRNA knockdown, immunofluorescence/nucleolar fractionation, ubiquitination assays, domain deletion analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — gain- and loss-of-function experiments with clear subcellular phenotype, domain mapping, single lab with two orthogonal approaches\",\n      \"pmids\": [\"20048074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"COMMD1 inhibits amiloride-sensitive current in mammalian epithelial cells via its COMM domain; COMMD1 increases ubiquitin modification of ENaC and decreases ENaC cell surface expression; COMMD1 interacts with SGK1 and Akt1, and its effects require Nedd4-2 (dominant-negative Nedd4-2 abolishes COMMD1 effects).\",\n      \"method\": \"Amiloride-sensitive current measurements in mammalian epithelial cells, surface biotinylation, co-immunoprecipitation, siRNA knockdown, dominant-negative constructs, ENaC PY-motif mutation\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — electrophysiology, surface biotinylation, Co-IP, multiple loss-of-function approaches, domain mapping; mechanistic pathway (Nedd4-2 dependency) established\",\n      \"pmids\": [\"20237237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Secretory clusterin (sCLU) acts as a ubiquitin-binding protein that enhances COMMD1 and IκB proteasomal degradation by interacting with SCF-βTrCP E3 ligase family members, thereby increasing NF-κB nuclear translocation; knockdown of sCLU stabilizes COMMD1 and IκB, sequestering NF-κB in the cytoplasm.\",\n      \"method\": \"Co-immunoprecipitation, proteasome inhibitor assays, siRNA knockdown, NF-κB reporter assay, microarray profiling\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, siRNA knockdown, reporter assay; single lab, mechanistic interaction identified\",\n      \"pmids\": [\"20068069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"COMMD1 interacts with SOD1 in a manner that requires CCS-mediated copper incorporation into SOD1; COMMD1 reduces the level of SOD1 homodimers without affecting disulfide oxidation; RNAi knockdown of COMMD1 significantly increases SOD1 activity and decreases superoxide concentrations, while overexpression has the opposite effect.\",\n      \"method\": \"Co-immunoprecipitation, SOD1 activity assay, RNAi knockdown and overexpression, superoxide measurement, dimerization assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, enzymatic activity assay, gain- and loss-of-function; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20595380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Liver-specific Commd1 knockout mice (Commd1^Δhep) develop hepatic copper accumulation (up to 20-fold on copper-enriched diet), providing the first genetic evidence for COMMD1's essential role in hepatic copper homeostasis in vivo.\",\n      \"method\": \"Liver-specific conditional knockout mice, biochemical and histological copper analyses, gene expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific genetic knockout with quantitative copper phenotype, in vivo model\",\n      \"pmids\": [\"22216203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"COMMD1 and clusterin independently regulate degradation of both ATP7A and ATP7B: COMMD1 facilitates ATP7B degradation via the proteasomal pathway while clusterin uses the lysosomal pathway; both proteins interact with ATP7B independently and non-competitively, and endogenous ATP7B exists in a complex containing both.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and knockdown, pathway-specific inhibitors (proteasome vs lysosome), endogenous complex analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pathway-specific inhibitors define distinct degradation routes, Co-IP, gain- and loss-of-function, multiple orthogonal methods\",\n      \"pmids\": [\"22130675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"COMMD1 regulates Cullin RING Ligases (CRLs) by antagonizing CAND1 binding: COMMD1 interacts with multiple Cullins, the COMMD1-Cul2 complex cannot bind CAND1, and COMMD1 can actively displace CAND1 from CRLs, promoting CRL activation.\",\n      \"method\": \"Co-immunoprecipitation, competitive binding assay, CAND1 displacement assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and competition binding assay, single lab, mechanistic displacement shown\",\n      \"pmids\": [\"21778237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"COMMD1 interacts with CFTR endogenously, promotes CFTR cell surface expression by protecting CFTR from ubiquitination, sustaining CFTR at the plasma membrane.\",\n      \"method\": \"Genetic screen, co-immunoprecipitation in cells with endogenous expression, surface biotinylation, ubiquitination assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — endogenous Co-IP, surface biotinylation, ubiquitination assay; single lab with multiple methods\",\n      \"pmids\": [\"21483833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"COMMD1 regulates δENaC through its COMM domain; co-expression of COMMD1 reduces δENaC surface expression and increases δENaC ubiquitination; COMMD1 promotes localization of δENaC to early/recycling endosomes.\",\n      \"method\": \"Co-immunoprecipitation, surface expression assay, ubiquitination assay, immunocytochemistry and confocal microscopy with endosomal markers\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — surface expression, ubiquitination, and localization assays; single lab, COMM domain requirement shown\",\n      \"pmids\": [\"21741370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Tumor suppressor ARF associates with COMMD1 and promotes non-classic Lys63-mediated polyubiquitination of COMMD1 in a p53-independent manner; this Lys63-linked ubiquitination does not target COMMD1 for proteasomal degradation; ARF redistributes from nucleolus to nucleoplasm upon DNA damage to interact with COMMD1.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitin chain-specific (K63/K48) analysis, deletion mapping of ARF, actinomycin D DNA damage, proteasome assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ubiquitin chain typing, Co-IP, domain deletion; single lab with multiple approaches\",\n      \"pmids\": [\"18305112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"COMMD1 binds to the C-terminal domain of NKCC1 (aa 1040–1134) via its N-terminus (aa 1–47) in airway epithelial cells and modulates NKCC1 ubiquitination and membrane expression; COMMD1 loss reduces baseline NKCC1 membrane expression and blunts hyperosmolarity-stimulated NKCC1 trafficking.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, Co-IP with endogenous proteins, siRNA knockdown, membrane expression assay, ubiquitination assay\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — yeast two-hybrid plus Co-IP plus functional knockdown; interaction domain mapped, single lab\",\n      \"pmids\": [\"23515529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"COMMD1 is directly linked to early endosomes through interaction with the CCC complex (CCDC22/CCDC93/C16orf62); the CCC complex interacts with the WASH complex subunit FAM21 via C-terminal ends of CCDC22 and CCDC93; depletion of CCC complex components prevents copper-dependent movement of ATP7A from endosomes, causing intracellular copper accumulation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, endosomal co-localization, copper accumulation assays, domain mapping\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, siRNA depletion, localization, copper assays; mechanistic pathway defined (CCC-WASH interaction), replicated with multiple CCC components\",\n      \"pmids\": [\"25355947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"p300 acetylates COMMD1, protecting it from XIAP-mediated proteasomal degradation; p300-mediated COMMD1 acetylation is required for COMMD1 to bind RelA under aspirin-mediated stress conditions but not TNF stimulation; this controls stress-specific (but not cytokine-driven) ubiquitination and nucleolar translocation of RelA.\",\n      \"method\": \"Co-immunoprecipitation, acetylation assays, siRNA knockdown, RelA nucleolar localization assay, stimulus-specific comparison\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — acetylation assay, Co-IP, stimulus-specific functional assays; single lab with multiple approaches\",\n      \"pmids\": [\"25074812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"COMMD1 modulates aggregation of misfolded SOD1 in a client-specific manner: COMMD1 enhances formation of mutant SOD1 (mSOD1) aggregates and co-localizes to mSOD1 inclusion sites, forming high molecular weight complexes; in contrast, COMMD1 decreases abundance of mutant Parkin inclusions and does not affect polyglutamine-expanded Huntingtin aggregation.\",\n      \"method\": \"Co-immunoprecipitation, co-localization by confocal microscopy, high molecular weight complex analysis, overexpression in cell models of ALS and PD\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-localization, HMW complex analysis, overexpression; single lab, client-specific effects documented with multiple substrates\",\n      \"pmids\": [\"24691167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DRR1, F-actin, and COMMD1 form a novel nuclear complex; stability of COMMD1 is enhanced within this complex; increased nuclear COMMD1 promotes NF-κB degradation; DRR1 and COMMD1 together suppress cyclin D1 expression, G1/S transition, and cell proliferation in neuroblastoma cells, with the DRR1-F-actin interaction being required.\",\n      \"method\": \"Co-immunoprecipitation, nuclear fractionation, NF-κB activity assay, cell cycle analysis, proliferation assay, DRR1-actin binding mutants\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP for complex, functional knockdown/overexpression with cell cycle readout; single lab with multiple methods\",\n      \"pmids\": [\"28604741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"COMMD1 in human macrophages restrains RANKL-induced NF-κB signaling and an E2F1-dependent metabolic pathway; hypoxia suppresses COMMD1 protein expression, augmenting RANKL-induced inflammatory and E2F1 target gene expression and osteoclastogenesis; myeloid-specific Commd1 deletion in mice increased osteoclastogenesis in arthritis and inflammatory osteolysis models.\",\n      \"method\": \"Myeloid-specific conditional knockout mice, RANKL stimulation, NF-κB reporter assays, E2F1 target gene analysis, arthritis and osteolysis mouse models, eQTL analysis\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with defined molecular pathway (NF-κB and E2F1-metabolic), multiple in vivo disease models, eQTL validation\",\n      \"pmids\": [\"28723554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"COMMD1 modulates copper-responsive ATP7B trafficking through recruitment to PtdIns(4,5)P2; decreased COMMD1 results in loss of ATP7B from lysosomes and trans-Golgi network under high copper; overexpression of a COMMD1 mutant deficient in PtdIns(4,5)P2 binding has little impact on ATP7B trafficking, demonstrating a PtdIns(4,5)P2-dependent mechanism.\",\n      \"method\": \"Quantitative colocalization analysis, COMMD1 PtdIns(4,5)P2-binding mutant, siRNA knockdown, copper export assay, organelle markers\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — mutant analysis plus co-localization, single lab with domain-specific mutation establishing PtdIns(4,5)P2 dependency\",\n      \"pmids\": [\"31515276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"COMMD1 is required for efficient repair of DNA double strand breaks and functions in both non-homologous end joining (NHEJ) and homologous recombination (HR) pathways, as determined by DSB reporter assays in COMMD1-siRNA-depleted cells.\",\n      \"method\": \"siRNA depletion, DSB repair reporter assays for NHEJ and HR, cell viability and cell cycle assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional DSB reporter assays with siRNA knockdown; single lab, two reporter systems\",\n      \"pmids\": [\"33669398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"COMMD1 reinforces HIV-1 latency in myeloid cells through IκB-α stabilization: COMMD1 induction in latently HIV-1-infected myeloid cells (via PI3K-JAK pathway) inhibits proteasomal degradation of IκB-α by increasing COMMD1-IκB-α interaction, attenuating NF-κB signaling during innate immune stimulation.\",\n      \"method\": \"Four pairs of latently HIV-1-infected and parental cells, Western blot, Co-IP, siRNA knockdown, PI3K-JAK pathway inhibitors\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP for COMMD1-IκB-α interaction, pharmacological pathway dissection, multiple cell line pairs; single lab\",\n      \"pmids\": [\"25520503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"An ATP7B splicing mutation (c.1543+1G>C) causes skipping of exon 3, producing mutant ATP7B with altered N-terminus that shows enhanced interaction with COMMD1 and is consequently degraded via the ubiquitin-proteasome pathway; this enhanced COMMD1 binding represents a universal pathogenic mechanism for ATP7B variants with altered N-terminus.\",\n      \"method\": \"Splicing assay, RNA pulldown, ATP7B-knockout HuH-7 cells, Atp7b-/- mice, co-immunoprecipitation, ubiquitin-proteasome pathway assay, intracellular copper measurement\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (splicing assay, Co-IP, KO cell and animal models), mechanistic pathway defined, single lab\",\n      \"pmids\": [\"39389536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"COMMD1 knockdown in ALS models enhances palmitoylation of the copper chaperone CCS via activation of the HIF-1α/FASN signaling axis, facilitating CCS membrane translocation and promoting copper loading into SOD1; in vivo, COMMD1 deficiency in hSOD1G93A transgenic mice ameliorates motor function deterioration and prolongs survival.\",\n      \"method\": \"siRNA knockdown, palmitoylation assay, membrane fractionation, HIF-1α/FASN pathway analysis, transgenic mouse model (hSOD1G93A), behavioral/survival assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway (HIF-1α/FASN-CCS palmitoylation) identified with multiple assays plus in vivo model; single lab\",\n      \"pmids\": [\"42156174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Crystal and cryo-EM structures of bacterial and archaeal COMMD-like proteins reveal homooligomeric ring assemblies of 8 or 10 subunits built from core dimeric building blocks with inter-dimer interactions analogous to the eukaryotic heterodecameric Commander complex COMMD ring; phylogenetic analysis indicates the closest relatives to eukaryotic COMMD proteins are found in Myxococcota bacteria.\",\n      \"method\": \"Cryo-EM structure determination, crystal structure determination, biophysical characterization, phylogenetic analysis (sequence + FoldSeek 3Di structural alphabet)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — high-quality structural methods (cryo-EM, crystal structure) but preprint, not peer-reviewed; establishes prokaryotic structural homologs\",\n      \"pmids\": [\"bio_10.1101_2025.09.01.673571\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"COMMD1 is a multifunctional scaffold protein that localizes to endosomal membranes via PtdIns(4,5)P2 binding and functions as part of the CCC-WASH complex to regulate endosomal trafficking of copper transporters (ATP7A, ATP7B); it promotes ubiquitin-proteasome-dependent degradation of multiple substrates including NF-κB RelA (via a Ser468-phosphorylation-dependent E3 ligase complex with Cullin 2), HIF-1α (by competing with HSP90β and preventing HIF-1α/HIF-1β dimerization), and misfolded copper transporters; its own stability is controlled by XIAP-mediated K48-polyubiquitination (degrading it) and p300-mediated acetylation (stabilizing it), and it directly binds Cu(II) with 1:1 stoichiometry via His101, His134, and Met110 in its exon-2-encoded region.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"COMMD1 (originally MURR1) is a copper-binding scaffold protein that couples copper homeostasis to endosomal protein trafficking and ubiquitin-proteasome-dependent degradation of multiple membrane and signaling substrates [#2, #8, #28]. It binds Cu(II) with 1:1 stoichiometry through His101, His134, and Met110 in its exon-2-encoded region [#8] and is recruited to endocytic-pathway vesicles by binding PtdIns(4,5)P2 through its C-terminal domain, where it forms large oligomeric complexes [#10]. Through the conserved COMM domain it engages homo- and heteromeric partners [#5], and it directly links to early endosomes via the CCC complex (CCDC22/CCDC93/C16orf62), which connects to the WASH-complex subunit FAM21 to drive copper-dependent endosomal movement of ATP7A; loss of CCC components causes intracellular copper accumulation [#28]. COMMD1 binds the copper-binding amino terminus of the Wilson disease protein ATP7B [#2, #7] and a PtdIns(4,5)P2-dependent mechanism governs copper-responsive ATP7B trafficking [#33]; it promotes proteasomal degradation of newly synthesized ATP7B, with disease-associated N-terminal mutations enhancing COMMD1 binding and accelerating degradation [#7, #36]. Liver-specific Commd1 deletion produces marked hepatic copper accumulation, establishing an essential in vivo role in copper homeostasis [#21]. In parallel, COMMD1 negatively regulates NF-\\u03baB: it acts at the chromatin level on NF-\\u03baB association [#5], and TNF-induced Ser468 phosphorylation of RelA/p65 recruits COMMD1 and Cullin 2 into a multimeric ubiquitin ligase that targets p65 for degradation and stress-induced nucleolar translocation [#12, #17]. COMMD1 also represses HIF signaling by binding the amino terminus of HIF-1\\u03b1, competing with HSP90\\u03b2 and blocking HIF-1\\u03b1/HIF-1\\u03b2 dimerization and transactivation [#15, #16]; Commd1-null embryos die with placental vascularization defects and elevated HIF-1\\u03b1 [#9]. Its own abundance is set by competing post-translational marks: XIAP binds the COMM domain and catalyzes K48-linked polyubiquitination driving degradation [#1, #14], while p300-mediated acetylation stabilizes it [#29]. More broadly, COMMD1 controls ubiquitination, surface expression, and trafficking of multiple ion channels and transporters including ENaC, CFTR, and NKCC1 [#3, #18, #24, #27], and antagonizes CAND1 to activate Cullin-RING ligases [#23].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established COMMD1/MURR1 as a negative regulator of NF-\\u03baB, defining its first signaling function via control of I\\u03baB-\\u03b1 stability.\",\n      \"evidence\": \"RNAi knockdown in primary resting CD4+ T cells with proteasome inhibition and NF-\\u03baB reporters\",\n      \"pmids\": [\"14685242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the direct molecular target or whether the effect was cytoplasmic versus nuclear\", \"Mechanism of I\\u03baB-\\u03b1 stabilization left unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected COMMD1 to copper biology by demonstrating direct interaction with the Wilson disease transporter ATP7B and opposing regulation by the ubiquitin ligase XIAP.\",\n      \"evidence\": \"In vitro binding and Co-IP for ATP7B; reciprocal Co-IP, K48 ubiquitin chain typing, Xiap-knockout mice and copper measurements\",\n      \"pmids\": [\"12968035\", \"14685266\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish where in the copper-excretion pathway COMMD1 acts\", \"Did not resolve whether COMMD1 affects ATP7B trafficking or stability\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Extended COMMD1's substrate range to ion channels by showing it inhibits ENaC-mediated sodium current, hinting at a general role in transporter regulation.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, Co-IP, and Xenopus oocyte electrophysiology with domain deletion\",\n      \"pmids\": [\"14645214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of channel inhibition not defined\", \"Performed in heterologous oocyte system rather than native epithelium\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined COMMD1 as the founding member of the COMM-domain family and localized its NF-\\u03baB effect to chromatin association rather than nuclear import.\",\n      \"evidence\": \"Biochemical interaction screen, Co-IP for complex formation, and ChIP\",\n      \"pmids\": [\"15799966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the ligase converting chromatin binding to p65 turnover\", \"Functional consequences of homo/heteromeric COMMD complexes unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Provided the first structural view of COMMD1, showing a novel alpha-helical N-terminal fold with surfaces suited to protein interactions.\",\n      \"evidence\": \"NMR solution structure of residues 1\\u2013108\",\n      \"pmids\": [\"17097678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the COMM domain and full-length protein not determined\", \"No partner-bound structure to define interaction interfaces\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified COMMD1 as a copper(II)-specific binding protein and clarified its role in ATP7B degradation, linking metal binding to substrate stability.\",\n      \"evidence\": \"EPR, UV-vis, fluorescence, DEPC modification, MS mapping, and mutagenesis for Cu(II) binding; GST pulldown, Co-IP, mutagenesis, and biosynthetic labeling for ATP7B\",\n      \"pmids\": [\"17309234\", \"17919502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not link copper binding mechanistically to ATP7B degradation or trafficking\", \"Did not identify the E3 ligase degrading ATP7B\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated an essential developmental role and a HIF-1\\u03b1-regulatory function, broadening COMMD1 beyond NF-\\u03baB and copper.\",\n      \"evidence\": \"Commd1 knockout mice, microarray, Co-IP, HIF-1 reporter and protein stability assays\",\n      \"pmids\": [\"17371845\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of HIF-1\\u03b1 destabilization not defined\", \"Embryonic lethality precluded analysis of adult phenotypes\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established the membrane-recruitment basis of COMMD1 function by identifying PtdIns(4,5)P2 binding through the C-terminus and endosomal localization with oligomerization.\",\n      \"evidence\": \"Co-localization, fractionation, lipid arrays, liposome binding, native PAGE, and modeling\",\n      \"pmids\": [\"18940794\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect lipid binding to a specific trafficking step\", \"Stoichiometry and composition of the oligomers unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Refined the regulation of COMMD1 stability, showing ARF promotes non-degradative K63 ubiquitination distinct from XIAP's degradative K48 marks.\",\n      \"evidence\": \"Co-IP, K63/K48 chain typing, ARF deletion mapping, DNA damage induction\",\n      \"pmids\": [\"18305112\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of K63 ubiquitination on COMMD1 activity not defined\", \"Single lab, ubiquitin chain typing not orthogonally confirmed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined a phosphorylation-gated ubiquitin ligase mechanism: Ser468-phosphorylated p65 recruits COMMD1 and Cullin 2 to drive p65 ubiquitination and degradation at target promoters.\",\n      \"evidence\": \"Phospho-specific mutagenesis, Co-IP, ChIP, ubiquitination assays, proteasome inhibition\",\n      \"pmids\": [\"19270718\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full subunit composition and substrate specificity of the ligase not enumerated\", \"Did not establish promoter selectivity rules\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified upstream regulators and additional pathways controlling COMMD1 levels and HIF repression, including HSCARG-driven degradation and HSP90-competitive HIF-1\\u03b1 destabilization.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, ubiquitination and redox assays (HSCARG); Co-IP competition, 17-AAG, ubiquitin-independent stability assays (HIF-1\\u03b1/HSP90\\u03b2)\",\n      \"pmids\": [\"19433587\", \"19802386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"HSCARG-COMMD1 ligase identity not defined\", \"Ubiquitin-independent HIF-1\\u03b1 degradation route mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Consolidated mechanism across NF-\\u03baB, HIF, ENaC, and SOD1: COMMD1 blocks HIF-1\\u03b1/HIF-1\\u03b2 dimerization, drives stress-induced RelA nucleolar targeting, regulates ENaC via Nedd4-2, and limits SOD1 activity.\",\n      \"evidence\": \"Co-IP, dimerization/luciferase assays and xenograft/metastasis models (HIF); nucleolar fractionation and ubiquitination (RelA); electrophysiology, biotinylation, Co-IP, dominant-negative Nedd4-2 (ENaC); SOD1 activity and dimerization assays\",\n      \"pmids\": [\"20458141\", \"20048074\", \"20237237\", \"20595380\", \"20068069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether a single COMMD1 complex serves all substrates is unresolved\", \"SOD1 and clusterin links rest on single-lab data\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided genetic proof of COMMD1's hepatic copper role and broadened its transporter clientele while defining its action on Cullin-RING ligases via CAND1 antagonism.\",\n      \"evidence\": \"Liver-specific conditional knockout with copper analyses; Co-IP and pathway-specific inhibitors (ATP7A/ATP7B, clusterin); endogenous Co-IP and biotinylation (CFTR, \\u03b4ENaC); CAND1 displacement assays\",\n      \"pmids\": [\"22216203\", \"22130675\", \"21483833\", \"21741370\", \"21778237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic basis for substrate-specific degradation route choice unclear\", \"CRL regulation not linked to a defined cellular output\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Anchored COMMD1 in the CCC-WASH endosomal trafficking machinery and clarified acetylation-controlled stability and stimulus-specific NF-\\u03baB regulation.\",\n      \"evidence\": \"Co-IP, siRNA, endosomal co-localization and copper assays (CCC/WASH); acetylation assays and stimulus-specific RelA assays (p300)\",\n      \"pmids\": [\"25355947\", \"25074812\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How COMMD1 selects copper-transporter cargo within the CCC complex remains undefined\", \"Acetylation site and its interplay with XIAP ubiquitination not fully mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked COMMD1 to physiological inflammatory and proliferative control in vivo through macrophage NF-\\u03baB/E2F1 regulation and a nuclear DRR1-actin complex.\",\n      \"evidence\": \"Myeloid-specific knockout mice with arthritis/osteolysis models and eQTL (macrophages); Co-IP, nuclear fractionation, cell-cycle assays (DRR1)\",\n      \"pmids\": [\"28723554\", \"28604741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic connection between copper trafficking and inflammatory phenotypes not established\", \"DRR1 complex function rests on single-lab data\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the ATP7B-degradation paradigm to a clinical mechanism, showing N-terminus-altering variants gain enhanced COMMD1 binding and accelerated proteasomal turnover.\",\n      \"evidence\": \"Splicing assay, RNA pulldown, ATP7B-knockout cells, Atp7b-/- mice, Co-IP, ubiquitin-proteasome and copper assays\",\n      \"pmids\": [\"39389536\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generalizability across all N-terminal variants relies on a single representative mutation\", \"Single-lab confirmation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated COMMD1 in genome maintenance and copper-dependent SOD1 disease pathways, including a HIF-1\\u03b1/FASN-CCS palmitoylation axis in ALS models.\",\n      \"evidence\": \"DSB reporter assays with siRNA (NHEJ/HR); palmitoylation, fractionation, pathway analysis and hSOD1G93A mice (CCS axis)\",\n      \"pmids\": [\"33669398\", \"42156174\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular role of COMMD1 in DSB repair not defined\", \"Connection between DNA repair and copper/trafficking functions unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single PtdIns(4,5)P2- and copper-binding scaffold integrates endosomal trafficking, multi-substrate ubiquitination, transcription-factor degradation, and DNA repair into one mechanistic logic remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of substrate selection within the Commander/CCC assembly\", \"Whether copper binding directly gates COMMD1's signaling functions is untested\", \"Physiological hierarchy among COMMD1's NF-\\u03baB, HIF, copper, and DNA-repair roles is undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 28, 12]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [10, 33]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [16, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [12, 23, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [10, 28, 25]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [4, 10]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 17, 31]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [28, 33, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 0, 16]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [2, 21, 28]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [12, 7, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 32]}\n    ],\n    \"complexes\": [\n      \"CCC complex (COMMD1/CCDC22/CCDC93/C16orf62)\",\n      \"COMMD1-Cullin 2 ubiquitin ligase\",\n      \"DRR1-F-actin-COMMD1 nuclear complex\"\n    ],\n    \"partners\": [\n      \"ATP7B\",\n      \"XIAP\",\n      \"RELA\",\n      \"HIF1A\",\n      \"CCDC22\",\n      \"CUL2\",\n      \"CFTR\",\n      \"NKCC1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}